Project Summary- Overall This application is for a new Program Project Grant entitled Integrative consequences of intermittent hypoxia?. Chronic intermittent Hypoxia (CIH) is a hall mark manifestation of sleep apnea, a highly prevalent respiratory disease affecting several million people in the USA alone. Patients with sleep apnea and rodents exposed to IH exhibit hyperactive sympathetic nervous system, which has been implicated in many of the pathologies caused by sleep apnea. The overarching goal of the proposed Program is to determine how CIH leads to sympathetic nerve activation and determine its consequences. Specific Aims of the program are: AIM 1- Determines the neural mechanism(s) contributing to sympathetic nerve activation by IH. Peripheral and central neural mechanisms associated with sympathetic activation by CIH which will be determined in Projects 1 and 2. AIM 2- Consequences of sympathetic activation by CIH, which will be addressed in Project 3 by determining the contribution of sympathetic activation to endothelial cell activation by CIH. AIM 3- Elucidates the epigenetic mechanisms underlying CIH-induced sympathetic nerve activation, which will be the focus of Project 4. All four Projects will be supported by an Administrative Core and a Scientific Core. Studies in this program utilize rodents exposed to an IH paradigm mimicking the blood O2 saturation profiles akin to those occurring during sleep apnea as well as in mice exhibiting natural sleep apnea. Conceptual innovation- Cellular and molecular mechanisms underlying the sympathetic activation by CIH proposed in this program are novel, which in addition to sleep apnea may also be applicable to other cardiorespiratory diseases. Major technical innovation includes assessing the significance of findings from experimental rodent model of IH in a naturally occurring sleep apnea mouse model. Investigators in this program have demonstrated expertise at the cellular, molecular, and systems levels of investigation and have strong record of collaborations. Completion of the program is anticipated to provide important insights for developing novel therapeutic strategies for alleviating autonomic co-morbidities associated with IH, which is a major manifestation of sleep apnea. Because of the tight thematic linkages across the projects, the total knowledge gained from the overall program will truly be greater than the sum derived from each project.